Acta Medica Marisiensis 2016;62(1):155-158
DOI: 10.1515/amma-2016-0003
CASE REPORT
Endocrine Dysfunction in Neurofibromatosis Type 1
– An Update
Pop Raluca-Monica1,2, Neagoe Radu Mircea3, Kolcsar Melinda4*, Paşcanu Ionela5
1 Research
Methodology Department, University of Medicine and Pharmacy Tirgu Mures, Romania
Endocrinology Outpatient Clinic, Emergency Mureş County Hospital, Tirgu-Mures, Romania
3 Surgery Department, University of Medicine and Pharmacy Tirgu Mures, Tirgu-Mures, Romania
4 Pharmacology and Clinical Pharmacy Department, University of Medicine and Pharmacy Tirgu Mures, Tirgu-Mures, Romania
5 Endocrinology Department, University of Medicine and Pharmacy Tirgu Mures, Romania
2
Background: Neurofibromatosis type 1 is an autosomal dominant disorder associated with multiple neoplasms particularly those of ectodermal origin. Various endocrine pathologies are often present, among them, hyperparathyroidism and follicular thyroid lesion are very rare
described and their coincidence in the same patient has not been described in the literature reviewed.
Subject: A 59-years-old woman with clinical manifestation of neurofibromatosis type 1 developed dysphagia, dysphonia, choking sensation.
Physical and imagistic examination revealed a multinodular goiter with microfollicular lesion on fine needle aspiration biopsy (FNAB), elevated
parathormone levels and severe osteoporosis. The surgically removed thyroid contained a nodule with follicular architecture of uncertain malignant potential; the parathyroid tissue appeared normal.
Discussion and conclusion: This case serves as a reminder to look for non-neurogenic tumors in patients with neurofibromatosis. Clinicians
must be aware of the diverse clinical features of this genetic disorder.
Keywords: follicular thyroid lesion, hyperparathyroidism, neurofibromatosis
Received 14 September 2015 / Accepted: 08 January 2016
Introduction
Neurofibromatosis is an autosomal dominant disorder that
affects the bone, the nervous system, soft tissue, and the
skin. At least 8 different clinical phenotypes of neurofibromatosis have been identified and are linked to at least
3 genetic disorders [1,2] Despite sharing a common name,
these are different phakomatoses both clinically and genetically. The most common form is neurofibromatosis type 1
(NF1) and it is diagnosed based on clinical criteria initially established by the National Institute of Health (NIH)
Consensus Development Conference on Neurofibromatosis in 1987. Neurofibromatosis type 2 is differentiated
from NF1 by the presence of vestibular schwannomas, juvenile cortical cataract and the missing “café au lait” spots.
Schwannomatosis is the third genetic disorder included in
the neurofibromatosis’ group. Its particular feature is represented by the presence of multiple schwannomas everywhere in the body, except the vestibular nerve [2].
Multiple neoplasms are associated with the features of
NF1, particularly those of ectodermal origin – astrocitomas, ependimomas, meningiomas, neurofibrosarcomas,
rhabdomiosarcomas, non-lymphocytic leukemia. Neurologic screening is part of the management of patients with
neurofibromatosis, considering the fact that clinical signs
increase over time.
Various endocrine pathologies are often associated with
neurofibromatosis. Short stature and growth hormone de* Correspondence to: Melinda Kolcsar
E-mail: [email protected]
ficiency are more common in these patients than in general
population, although the exact incidence is not known.
Precocious puberty, usually caused by a hypothalamic or
optic nerve glioma is reported in 3.5% of the patients.
Other endocrine neoplasms related to neurofibromatosis
are: pheocromocytoma, hyperparathyroidism, somatostatin producing carcinoid tumors of the duodenal wall, medullary thyroid carcinoma (3). Non-neurogenic tumors are
also associated with neurofibromatosis (1).
Case example
A 59 years-old woman presented in our department with
complaints of dysphagia, dysphonia, choking sensation.
She was previously diagnosed with NF1, premature ovarian failure and multinodular goiter. Initial physical examination revealed short stature, a dimorphic facies, more
than 20 “café au lait” spots, multiple neurofibromas, dispersed all over the body (Fig.1), with axillary and inguinal
freckling, pain on percution of the lumbar spine. The thyroid was slightly enlarged, with a 1.5 cm nodule palpable
in the left lobe.
The thyroid ultrasound confirmed the presence of multiple nodules, in both lobes, the largest one of 1.5 cm,
in the isthmus, hypoechoic with intense Doppler signal which also had decreased uptake on scintiscan. The
FNA cytology report stated a class 4 Bethesda lesion with
consequent recommendation of surgical removal of the
nodule. Figure 2a emphasizes the characteristic cytoarchitectural pattern of a follicular neoplasm. It shows several
microfollicular cell groups in a clear background (absence
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of colloid). At higher magnification the nuclei of these
structures are increased in size, slightly pleomorphic and
overlapped but they are round, regular, with a homogeneous chromatin. In some nuclei a centrally placed nucleolus can be visible (Fig. 2b).
Prior to surgery we screened for other known associations of NF 1 with neurological and endocrine disorders
and found elevated parathormone values (182.9 pg/ml),
with normal calcium (9.17 mg/dl) and low phosphorus
levels (2.39 mg/dl), osteoporosis with low T scores on bone
densitometry, consistent with the diagnosis of primary
normocalcemic hyperparathyroidism. However, the parathyroid scintiscan did not reveal any abnormal findings.
Normal computed tomography imaging has ruled out any
cranial manifestation of NF1 and urinary metanephrines
levels within normal range excluded the pheochromocytoma.
After the clinical and paraclinical evaluation, total thyroidectomy with subtotal parathyroidectomy was performed. The pathological report showed in a background
of chronic lymphocytic thyroiditis, an isthmic tumor with
uncertain malignant potential. At low magnification this
lesion was encapsulated and had an exclusively follicular
pattern of growth with follicles of different sizes, sometimes irregular in shape (Fig. 3). At high magnification,
some follicles have round and regular nuclei, with homogenous chromatin and others have nuclear clearing, irregularities of the contours and sometimes rare grooves (Fig. 4).
There was no capsular or vascular invasion present.
Post-operatively, the patient developed severe hypocalcemia, which was corrected with calcium infusion. The
evolution afterwards was favorable, with no recurrence 5
years after surgery.
Fig. 2a. The FNA aspect of the follicular neoplasm
Fig. 2b. The aspect of the nuclei in FNAB with higher magnification
Fig. 3. The follicular pattern of the tumor
Fig. 4. The aspect of the nuclei with high magnification
Fig. 1. Neurofibromas in the abdominal region
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Discussions
NF1 is one of the most frequent genetic disorders, its prevalence ranging from 1/2000 to 1/5000 in most population based studies [2]. The disease is caused by NF1 gene
mutations, located on chromosome 17q11.2. The protein
encoded by this gene, neurofibromin, is tumor suppressor
– a negative regulator of the Ras signal transduction pathway. More than 500 different mutations of the NF1 gene
have been identified. Most mutations are unique to a particular family. More than 80% of the germline mutations
described in individuals with neurofibromatosis appear to
cause severe truncation of the gene product. NF1 is characterized by extreme clinical variability, not only between
unrelated individuals but also among affected individuals
within a single family. There is no apparent link between
the mutations and the clinical manifestations.
The endocrine abnormalities most often associated with
neurofibromatosis are precocious puberty, pheocromocytoma, hyperparathyroidism, carcinoid tumors [3]. Specific
recommendations for surveillance of patients with NF-1
for other endocrine tumors do not exist. The exact prevalence of hyperparathyroidism in neurofibromatosis patients is not known. There are some reports recommending the screening of all patients with neurofibromatosis for
this association [4-10]. The bone lesions described in neurofibromatosis are similar to those found in hyperparathyroidism [11,12]. Our suspicion of hyperparathyroidism,
based on the high PTH values with normal calcium, low
phosphorus and osteoporosis could not be confirmed by
the pathological report, the parathyroid tissue sent for
analysis appearing normal. We can conclude that this was
a secondary hyperparathyroidism, maybe due to hypovitaminosis D and osteomalacia (25-OH vitamin D value
was not available), another disorder described in association with NF 1 [13]. We know that NF1 is one of the
most often encountered component of multiple endocrine
neoplasias, so, its diagnosis implies the search for other
endocrine abnormalities. The association of ectodermal
and non-ectodermal derived tumors has been proved, with
concomitant features of MEN syndromes and neurofibromatosis present in some cases [14-16], none of which
being diagnosed in our case.
There are only a few reports concerning the association
of a thyroid lesion with neurofibromatosis [17]. Thyroid
malignancies have been described in association with NF1,
most often medullary thyroid carcinoma, in some cases
associated with pheochromoctoma and primary hyperparathyroidism [14,16].
A follicular lesion of the thyroid is a common diagnosis
on FNAB, without the possibility to ascertain its outcome,
so surgical treatment is often indicated. The Bethesda classification has improved the management of follicular lesions, although they remain the pitfall of FNAB [18]. In
our case the decision for total thyroidectomy was based on
the ultrasonography description, the patient’s symptoms
and the expected difficulty in case of a second intervention
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due to multiple neurofibromas in the anterior cervical region. Also, the suspicion of primary hyperparathyroidism
lead to the choice of surgical treatment. The final pathological description of the nodule was tumor of uncertain
malignant potential, without the possibility to ascertain
the biologic potential of the lesion. The term “thyroid tumor of uncertain malignant potential” (TT-UMP) is used
by pathologists for describing well-differentiated tumors
(WDT) showing inconclusive morphological evidence of
malignancy or benignity.
The recommendation is that this term should be used
only for adequately sampled tumors, when there is real
uncertainty about whether the criteria for invasion have
been met [19,20]. A recent study proposes major and minor criteria for the diagnosis of this type of tumors [21].
Based on these criteria, the patients’ tumor is categorized
of WDT-UMP. Several studies were performed searching
for immunohistochemistry modifications which could be
used as markers for these tumors’ outcome. None of them
showed conclusive results [22,23]. It has to be mentioned
that DNA microarray gene analysis on thyroid tumors
successfully discriminated benign and malignant tumors
including borderline lesions [24]. Continuous progress in
molecular studies on thyroid tumors hopefully will determine the emergence of a useful diagnostic tool in the future.
This type of tumors are the “grey zone” of thyroid lesions and from the clinical point of view, it complicates the
future management of our patient. There is no treatment
protocol or a consensus regarding the post-operative follow-up for this type of lesion. Although radioiodine treatment is not indicated, the potential for metastases or recurrence is not known and careful follow-up is recommended
[20]. There is no express recommendation for suppressive
doses of levothyroxine or a clear timeframe for ultrasound
studies. Our opinion would be to administer adequate doses of levothyroxine in order to keep the TSH level in the
lower normal range and to perform at least annual checkups, including ultrasound and, maybe, thyroglobulin level.
In order to better classify and treat this type of tumors,
further studies are needed, regarding the survival rate or
the metastases percentage.
In summary, we described the case of a 59 years old
woman with neurofibromatosis who associated a thyroid
tumor of uncertain malignant potential and secondary hyperparathyroidism. Although this association can be simply a coincidence, prompt diagnosis is necessary in order
to provide optimum care for our patients with neurofibromatosis type 1 .
Conclusions
The association of thyroid lesions should be sought in patients with clinical features of neurofibromatosis and an
ultrasonography of the thyroid gland should be performed.
Although hyperparathyroidism caused by an adenoma is
described in patients with NF1, other causes of elevated
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PTH values should be sought also. Clinicians must be
aware of the diverse clinical features of this genetic disorder.
Acknowledgement
We would like to thank Professor Angela Borda from the
Histology Department of the University of Medicine and
Pharmacy Tirgu Mures for the pathology images and their
interpretation.
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